JPH0443224B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Nuclear magnetic resonance (hereinafter referred to as NMR) is a relatively recent method in radiology for studying and imaging intact biological systems. Like X-ray and ultrasound methods, NMR is a non-invasive analytical technique used as a means to examine the body. However, unlike X-rays, NMR is a non-ionizing, non-destructive method that can be used continuously on subjects. Furthermore, NMR imaging can provide anatomical information that can be comparable to that provided by an X-ray CAT scan. Compared to ultrasound method,
The image quality of the reconstructed projections or images from currently known NMR techniques rivals or exceeds that observed by ultrasound methods. Therefore, these rather unusual and highly desirable features give NMR the potential to become one of the most versatile and useful diagnostic tools ever used in today's biological and medical communities. It is growing.

Basically, NMR is a process that occurs when a magnetic field is applied to a nucleus that has a magnetic moment. If electromagnetic radiation in the high frequency region of the spectrum is then applied, the magnetized nuclei will emit a detectable signal with a frequency similar to that applied.

More specifically, NMR is based on the fact that many nuclei have an inherent magnetism, or spin, resulting from the angular momentum of such nuclei. Similar to bar magnets, the nature of spin creates a magnetic dipole or moment around such a nucleus.
In this way, when two external fields are applied to an object, a strong magnetic field will cause a dipole for such a nucleus, e.g. Align it either way.
Of these two orientations, parallel alignment is more stable because the nucleus only needs to store less energy.
Or the dominant orientation. For a second applied field consisting of radio frequencies with the correct frequency or quantum of electromagnetic radiation, this field will nutate or flip such nuclei to a more unstable orientation. In an attempt to reestablish a dominant parallel or stable orientation, the excited nuclei emit electromagnetic radio waves at a frequency nominally proportional to the magnitude of the strong field, but clearly characteristic of its chemical environment.

Accordingly, NMR techniques detect radio frequency signals emitted by a nucleus as a result of the processes that such a nucleus undergoes when exposed to at least two externally applied fields. If a third magnetic field is applied in the form of a gradient, nuclei with the same gyromagnetic constant will nutate at different frequencies, ie the Larmor frequency, depending on their position within the object. In this way, similar nuclei in the object can be calculated using the following formula fo = (γ) Ho
(where fo is the Larmor frequency, γ is the gyromagnetic constant, and Ho is the applied magnetic field) depending on the strength of a particular magnetic field along the applied magnetic gradient. According to their Larmor frequencies, individual regions in the object can be detected separately.

Unfortunately, there are several factors that limit the usefulness of NMR applications in living organisms. In general, NMR is a radiological characteristic of low sensitivity that requires the presence of meaningful quantities of nuclei with magnetic moments in the object. Therefore,
Not all nuclei in living organisms are present in sufficient quantities to be detected by current NMR techniques. Furthermore, not all nuclei in living organisms have magnetic moments. Some common isotopes without magnetic moments found in living organisms include carbon-12, oxygen-16, and sulfur-32.
Thus, current NMR applications in living organisms are limited to nuclei that have magnetic moments and are present in sufficient quantities to overcome the low sensitivity of current NMR techniques.

Traditionally, applications of NMR in living organisms have almost exclusively involved imaging or sensing the distribution of water within a region of interest derived from the detection of proton resonances. Other nuclei not only have lower inherent NMR sensitivities but are also less abundant in biological materials. However, the use of other nuclei such as phosphorus-31 has been considered, and its high natural abundance in biological fluids makes it the next best choice after NMR for biological applications. represents the elements For example, phosphorus-31 NMR simply measures the chemical shift of the inorganic phosphate resonance in vivo, and from the standard titration curve the PH or
It has been found that determining Mg ⁺⁺ concentration provides an indirect means of measuring intracellular PH and Mg ⁺⁺ concentration. Type of information obtained from NMR.IN: Gazian, D. G.
(Gadian, DG): Nuclear Magnetic
Resonance and Its Applications to Living
Systems, first edition, oxford:
Clarendon Press, 23
~42 pages (1982); Moon, R. Bee (Moon,
RB) and Richard, J. Etsuchi (Richards, JH): Determination of
Intracellular PH By ³¹ P Magnetic
Resonance, J.Biological Chemistry, 218
(20):7276–7278 (October 25, 1973). Furthermore,
Sodium-23 was used to image a heart perfused with a medium containing 145 mM sodium in vivo. Unfortunately, difficulties arise with these nuclei because their low resonant frequencies result in a loss of inherent sensitivity. Moon, Earl. B. and Richard, J.A. Etsuchi. :Determination of Intracellular PH By
³¹ P Magnetic Resonance，J.Biological
Chemistry.218(20):7276-7278 (October 25,
1973).

Another stable element that is uniquely suited for NMR imaging is fluorine because its inherent sensitivity is virtually comparable to that of protons.
It gives a relatively uncomplicated and well-resolved spectrum with 1/2 spin, and its natural isotope abundance ratio is
100 percent, because it gives a large chemical shift, and because its gyromagnetic constant is similar to that of protons, the same equipment can be used. Unfortunately, fluoride to living organisms
The application of NMR is virtually impractical since there is virtually no fluorine in biological materials that can be observed by NMR methods commonly used in the study of biological systems. However, the positron emitter is
Nuclear medicine methods using 18 are well provided with relevant information, including, for example, bone scanning, brain metabolism and infarct studies using fluorodeoxyglucose, and myocardial perfusion and metabolism. Regarding the fluorine-containing NMR imaging method, some research has been conducted into such applications. Suggestions are provided including the study of vascular disorders with fluorinated hydrocarbon blood substitutes, Holland, G.I. Holland, GN et al., ¹⁹ F.
Magnetic Resonance Imaging, J.Magnetic Resonance, 28:
133-136 (1977), and suggestions involving the localization/kinetics of perfluorinated hydrocarbons after liquid respiration were also submitted. Additionally, an in-vessel dog study was performed to investigate the potential of fluoride as an agent for NMR imaging of myocardial infarction. The principles cited above and research directed to fluorine elements are published in Thomas, S. Thomas, SR, etc.: Nuclear Magnetic
Resonance Imaging Techniques Developed
Modestly Within a University Medical
Center Environment: What Can the Small
System Contribute at this Point?
Magnetic Resonance Imaging, 1(1): 11-21
(1981). Additionally, NMR techniques in non-animal objects have been described for the determination of the magnetic susceptibility of oxygen in benzene or hexafluorobenzene solutions to calculate the amount of dissolved oxygen. For example, this method could be used for remote control of oxygen content in organic solvents for oxygen pressures greater than 1 atmosphere. Derpetsk, J. J.A.
(Delpuech, JJ), Hansa, M. A.
(Hanza, MA) and Serratrice, G.: Determination of Oxygen.
By a Nuclear Magnetic Resonance
Method, J. Magnetic Resonance, 36: 173~
179 (1979). Finally, in objects other than animals
Regarding NMR techniques, the solubility of oxygen (expressed in mole fraction) was demonstrated to be higher in fluoroalkanes than in hexafluorobenzene as previously reported. Hansa, M. A. etc:
Fluorocarbons as Oxygen Carriers. An
NMR Study of Partially or Totally
Fluorinated Alkanes and Alkenes, J.
Magnetic Resonance, 42:227–241 (1981).

Studies directed at conformational equilibrium and establishment of equilibrium by NMR spectroscopy have been carried out, particularly on cyclohexane and fluorocyclohexane rings.
In such applications, measurements of the position of equilibrium between conformers and the rate of equilibrium establishment of such isomers as a function of temperature have been determined. However, these studies relied on the use of known temperatures to measure equilibrium and equilibrium rates. Roberts, J. Day. :Studies of
Conformational Equilibria and Equilibration
by Nuclear Magnetic Resonance
Spectroscopy, Chemistry in Britain, 2:529
~535 (1966); Homer, J. (Homer, J.)
and Thomas, L. F. (Thomas, L.
F.): Nuclear Magnetic Resonance Spectra
of Cyclic Fluorocarbon，Trans.Faraday
Soc.59:2431–2443 (1963). Furthermore, carbon-13
It was shown that it can be used as a kinetic thermometer in a laboratory environment. This particular application requires that the test system contain at least two chemically exchanged sites corresponding to one exchange process, and that the carbon-
In order for 13 to serve as a kinetic thermometer it is necessary to include an independent means of determining the kinetic parameters that describe the exchange process. However, such applications are limited to temperature measurements in coalescence and thus can only work at one temperature for each independent exchange process, as opposed to over a continuous range. Furthermore, this method is used as a calibration technique. Furthermore, this accuracy is not inherently reliable enough to be of any practical importance. Sternherr, S. (Sternhell, S.): Kinetic ¹³ C
NMR Thermometer, Texas A&M
University NMR Newsletter, No. 285: 21-23
(June 1982).

Temperature has been measured using NMR spectra of liquid samples for the purpose of calibrating the temperature controllers of NMR spectrometers. Many features of NMR spectra, such as chemical shifts, often exhibit weak temperature dependence and can be used to measure temperature. Bornais, Jr. and Brownstein, S.: A Low
−Temperature Thermometer for ¹ H, ¹⁹ F,
and ¹³ C, J. Magnetic Resonance, 29: 207~
211 (1978). In this particular citation, the separation of peaks and spin-spin coupling in proton NMR spectra of liquid test samples is observed at a temperature of 20.5 °C.
changes by 1.75Hz and 0.07Hz, respectively. The best spectral resolution obtained is 10
to 50Hz or greater, and the temperature to 1
Such temperature measurement means cannot be applied to objects that need to be measured to a degree of accuracy of 2°C or 2°C, such as animals.

Regarding temperature in animals, it is well known that temperature is an excellent clinical indicator for clinicians regarding the health status of animals. For example, abnormal fluctuations in temperature, such as a rise in temperature, may reflect infection or hyperthermia, while a drop may indicate ischemia or hypothermia. Therefore, there is a need to accurately, inexpensively, and reliably measure the temperature of animals. Traditionally, temperature measurements have generally consisted of invasive and cumbersome techniques, which often result in less than reliable measurements. For example, current technology consists of penetrating needles, wires, cables, or instrumentation that must be inserted into the area of interest. Such piercing procedures unfortunately have the potential for chemical and biological contamination of the subject.
Thus, reuse of temperature sensing instruments requires proper preparation and sterilization procedures to prevent contamination by transmission and corrosion. Another drawback inherent in the conventional technique is the discomfort and inconvenience experienced from contact with the penetrating probe. Therefore, accuracy and reliability can be an unfavorable compromise with these conventional techniques. For extremely delicate structures, temperature cannot be obtained without sacrificing the integrity of the structure. Generally, the structure is damaged, displaced, or its dimensions changed.
There is another possibility of shorting out the instrumentation used, which further adds cost and time to the procedure. Yet another drawback is the instrument's own sensitivity when exposed to physical and chemical extremes that may impede its reliability. Finally, conventional techniques cannot measure a continuous temperature field in an object or animal, thus requiring two invasive and laborious procedures for each time or point in space at which temperature measurements are desired. This requires multiple temperature sensors or multiple temperature sensors to be used at the same time.

measurement of temperature in an object or animal
From the above brief overview and current state of knowledge directed to the limitations of NMR technology and various methods to more effectively and advantageously sense, measure and continuously monitor the temperature of objects or animals. It is clear that there is a need to provide improved methods to do this.

The present invention is directed to a novel method of sensing the temperature of an object using nuclear magnetic resonance (NMR) technology. Essentially, the novel method is based on an element derived from a compound having at least one conformer present in the object or combined with the object, which compound is affected by temperature. The temperature of an object is indirectly detected by observing the detected radio frequency signal and comparing the detected signal as a means of detecting the temperature of or within the object. The difference between the positions of the lines of the detected signal derived from the elements of a compound with conformers, or the rate at which interconversion occurs, or the intensity of the lines, i.e. the spectral lines, is a distinct method for detecting the temperature in an object. parameters. Furthermore, the temperature in the object can be determined from the detection signal derived from the element by the relaxation time, e.g. spin-lattice relaxation time T ₁ or spin-
It can also be detected from the spin relaxation time T ₂ . Other parameters that can be used to detect the temperature in an object are the spin-spin coupling derived from the detected signal of the element of a compound with conformers, or the environment in which quadrupolar coupling appears in its spectrum. In the case of such compounds, and if the element investigated can exhibit quadrupolar bonding, it is quadrupolar bonding.

One major advantage to this method is that temperature can be detected in animals. Another major advantage is that by utilizing NMR techniques in accordance with the principles of the present invention, temperature can be sensed non-invasively, non-destructively and continuously. Yet another advantage of the method of the invention is that the temperature in the object or animal can be visualized in a one-dimensional, two-dimensional or three-dimensional projection.

Therefore, one object of the present invention is to
The NMR spectrometer detects radio frequency signals derived from the elements of the compound present in the object or in combination with the object in which the compound has at least one conformer that is affected by temperature; It is an object of the present invention to provide a method for sensing the temperature of at least one object, which consists in comparing the detected signals as a means for sensing the temperature. The difference between the signals detected for the same element, or the spectral position or chemical shift, corresponds to the temperature of the object. Furthermore, the intensity of each detected signal, representative of the concentration or amount of each conformer, also corresponds to temperature. Furthermore, the rate at which interconversion occurs between conformers also depends on temperature. Furthermore, differences in spectral position or chemical shifts, relaxation times, e.g. T ₁ or T ₂ , spin-spin coupling or quadrupolar coupling provide other means of determining the temperature in the object. Once a spectral position or chemical shift, relaxation time, spin-spin coupling or quadrupolar coupling is observed for an element in a compound that has conformers that are influenced by temperature; A standard NMR spectrum determined and established for an element in the presence of a known varying temperature, or chemical shift, relaxation time, spin, as a means of determining at least one temperature in the object. - Comparable to spin or quadrupolar coupling. In effect, temperature can be determined from the exchange rates or equilibrium constants between conformers, differences in spectral lines, and changes in relaxation times, spin-spin and quadrupolar coupling.

According to the method of the present invention, the element detected is fluorine, but is not limited to this. When the element to be detected is fluorine, a sufficient amount of fluorine is used to detect perfluorinated hydrocarbon compounds or any derivatives thereof, and more preferably perfluorocyclic hydrocarbon compounds, from compounds having conformational isomers. introduced into animals as a means of feeding them. An example of such a perfluorocyclic hydrocarbon compound is perfluorodecalin. Artificial blood compositions incorporating suitable perfluorinated hydrocarbon compounds can also be used.

Furthermore, the present invention further processes detection signals derived from elements of a compound that has conformers and is affected by temperature or is combined with the target object, thereby detecting the target object. The method is based in part on providing at least one projection (dimension) of at least one temperature of the temperature while also providing a high resolution two-dimensional spatial map (image). The detected signals can be further used to reconstruct a one-dimensional, two-dimensional, or three-dimensional temperature image. The images show chemical shift, relaxation time, and spin.
It can be derived from spin coupling or quadrupolar coupling. Thus, the present invention provides a non-invasive, non-destructive method for creating one-, two-, or three-dimensional thermal maps in animals in vivo. Furthermore, according to the present invention, similar capacitive NMR thermographic images can be obtained from objects other than animals. In practicing the method of the invention, this novel method can be used to continuously measure and monitor the thermal physiological status of an animal or an object in vivo.

It is hereby acknowledged by the inventors that US Pat.
However, even though such methods for imaging chemical shifts have been reported, it is still unclear that such methods are uniquely effective for indirectly imaging temperature within objects or animals. It was unknown to me. Furthermore, such discoveries and other advantages of the present invention and its uses described herein are believed to be unexpected and not readily apparent, and may be learned from the detailed description below. It will become even clearer.

In a presently particularly suitable embodiment, the implementation of the novel method according to the invention for detecting at least one temperature of an object or in an object comprises:
NMR spectral examination of detected elements in a temperature-influenced object is used to determine the temperature of or within the object. Such tests include spectral positions or chemical shifts derived from radiofrequency signals for elements of a compound with temperature-influenced conformers, relaxation times, e.g. T ₁ and T ₂ , spin-spin coupling and The temperature of the object is determined from the quadrupolar coupling. Conformers are defined as a related set of internal rotations, bends, translations, or associated arrangements or juxtapositions of molecular or ionic moieties or chemical forms of a compound, or in the detailed description of the invention. molecules of the compound in a crystal lattice or other similar microscopic environment such that exchange or interconversion between members of said set causes exchange narrowing or other effects in the described NMR spectra. Refers to either a set of related positional orientations, translations or other arrangements of ions. Measuring the temperature of an object using the NMR technique and principle of the present invention has never been done before. Essentially, the novel method according to the invention indirectly determines at least one temperature in an object by its effect on the spectrum, i.e. the chemical shift, relaxation time, spin-spin coupling and quadrupolar coupling of the detected elements. Detect accurately. The teachings of the present invention can also be applied to animals to measure temperature within the animal.

What is chemical shift? Glossary: Kaofman, L. ，
Kurtkus, L. E. and Margulis, A. Kaufman, L., Crooks, LEand
Margulis, AR): Nuclear Magnetic
As defined in Resonance Imaging in Medicine, 1st edition, New York-Tokyo: Igaku Shoin, p. 233 (1981), it refers to the shielding effect that electron orbital motion has on the magnetic field in a certain nucleus.
The chemical shift is therefore directly proportional to the applied magnetic field and is observed as a somewhat shifted peak on the spectrum. Chemical shift can further be defined as the difference between the strength of the external magnetic field and the local magnetic field created at the selected element being detected. Therefore,
The horizontal position of the spectral line or resonance is determined by the chemical identity of the group in which the observed nucleus resides. For example, if an element in the structure of a compound is detected, the temperature of said compound is such that the rate of interconversion between the conformers is much greater than the chemical shift separation of the spectral lines of the conformers measured in Hz. low enough that the position of each resonance in the spectrum for that element will be correlated with a particular conformer of the compound. In other words, the environment surrounding the detected element of a certain compound is different for each conformational isomer. Therefore, the different horizontal positions of the spectral lines reflect the chemical shifts that exist for the element being detected and are expected for that element. If the temperature of the compound is sufficiently high that the rate of interconversion between the conformers is much greater than the separation of the chemical shifts of the spectral lines of the conformers at sufficiently low temperatures, then the The NMR spectrum of a compound exhibits only one single spectral line with the spectral position of the spectral line determined by the chemical shift at a sufficiently low temperature and the amount of each conformer present at a sufficiently high temperature. Probably. As the temperature of a compound changes continuously between high and low temperatures, its NMR
The spectra will show corresponding continuous changes between the high and low temperature extreme spectral shapes. This effect is known as exchange averaging or exchange narrowing. The advantage of the present method over previous thermometry methods by NMR is that the rate of interconversion between conformers can be a very strong function of temperature, resulting from varying the temperature of compounds exhibiting exchange narrowing. The spectral change can be much larger than the spectral change that would occur if exchange narrowing did not occur. Spectral changes that do not include exchange narrowing are not applicable to temperature measurements in objects or animals whose spectral resolution is stepwise worse than in typical chemical test samples, whereas spectral changes that exhibit exchange narrowing are It can be used to measure the temperature in an object or animal to a high degree or accuracy. Other spectral features, such as spin-spin coupling, quadrupole coupling and relaxation time, exhibit similar behavior when compounds undergo exchange narrowing and can be used to detect temperature as well.
Therefore, according to the principles of the present invention, it should be understood that the spectrum will correspond to the temperature in the object since the interconversion between the conformational forms of a compound characterizes the temperature. be.

Furthermore, since the relative abundance of each conformer is correlated with temperature, the relative intensities of the spectral lines of each conformer at temperatures low enough that exchange narrowing does not occur will characterize the temperature. . Furthermore,
The spectral position of a compound that has conformers at temperatures high enough for exchange narrowing to occur will be correlated with the relative amounts of each conformer, so that the spectral position of the compound will characterize the temperature. These two effects have a strong and useful temperature dependence when the thermodynamic Gibbs free energy difference ΔG between the conformers divided by the common gas constant R is comparable in magnitude to the absolute temperature T. Probably.

For detected elements of a compound having at least one conformer, once a spectrum,
For example, if a chemical shift is observed, the temperature of the object in combination with the compound is determined by (1) the spectral line as a measure of the rate at which the interconversion or exchange of isomers occurs; (2) the temperature of the object in combination with the compound; It can be determined, but is not limited to, the intensity, or amount, of the spectral lines; and (3) the distance between horizontally located spectral lines for each isomer as a reflection of the direct temperature determined from the spectrum. Despite the temperature dependence for all three parameters,
The determination of temperatures from all three methods is derived from the principle that compounds with at least one conformer interconvert uniquely at different temperatures. Because conformers interconvert, the rate at which interconversion of isomers occurs, the distance between the spectral lines for each isomer, and its intensity, or amount of each isomer, all depend on temperature. Therefore, according to the principles of the present invention, the shielding effects derived from the environment surrounding one element of the delivery isomers are different, and the rate of exchange between the conformers corresponds to the temperature in the object. It should be understood that the distance between the horizontal positions of the spectral lines as well as the relative intensities, or amounts, of the spectral lines of each isomer also correspond to temperature. Therefore, measurement of the spectra or chemical shifts for elements of a compound with delivery isomers provides a determined temperature in an object or animal in at least three ways.

Therefore, to measure the temperature in an object or animal, one must determine the rate of exchange between the isomers, the strength or amount of the isomers, and the distance between the horizontal positions for each isomer (all of which simulate temperature).
Perform mathematical calculations to measure. When determining the temperature by the exchange rate between isomers, the exchange rate k, or number of interconversions/second, is determined by the chemical shift in Hz, as opposed to ppm (parts per million). Must be compared based on the difference δ. When k is larger than δ, only one single horizontal line is observed at the concentration-basis mean shift value. When k is smaller than δ, horizontal independent lines are seen at each value for each conformer. Therefore, the rate of exchange or interconversion is directly related to the spectrum, which is a reflection of temperature. Starting from a low exchange rate or temperature and increasing the rate with higher temperature, the independent spectral lines move towards each other, become wider, and finally coalesce at the high exchange rate. Produces a single sharp line. One example of a mathematical calculation for determining k using the teachings of the present invention concerns the slow exchange side of coalescence. In this way, the line separation can be done, for example, by: (where δ is equal to the line separation in Hz and δ ₀
is equal to the separation of the lines in Hz in the low speed limit). The above equations are for illustrative purposes and are applicable to some limited situations that are satisfied in accordance with the principles of the present invention. In this way, if δ is determined for a compound in the object by NMR techniques according to the method of the invention and δ ₀ is known for that compound, then the exchange rate k for that compound can be determined. . Once determined, the exchange rate h for that compound can be compared to a predetermined exchange rate for a particular compound corresponding to a known temperature, for example, or to detect the temperature at the object. The NMR apparatus can then be calibrated to a known temperature that corresponds to the exchange rate k. Ideally, the aim of the invention is to detect elements of compounds that are on the slow exchange side but close to coalescence when trying to measure small temperature changes. Furthermore, when measuring temperature in an animal, it is preferred that the compound is at a slow exchange rate at physiological temperature. In other words,
Such compounds should generally be "sensitive" compounds in which readily discernible, well-resolved spectral shifts are usually observed when there are relatively small temperature changes.

Mathematical calculations can also be performed if the temperature is to be determined from the spectral line intensities derived from the spectrum. total area under the spectral line,
Alternatively, the line integral is proportional to the number of nuclei of a particular isomer detected. The intensity of each spectral line therefore corresponds to the amount of each isomer of the compound in a particular form existing at a particular temperature. Therefore, the intensity of the spectral lines as well as the exchange rate, and more specifically,
The average intensity of the spectral lines represents a uniquely characteristic temperature for each compound. One example of a mathematical calculation similar to that of exchange rates that can be used in accordance with the teachings of the present invention is to determine the equilibrium constant K, or ratio, between conformers: equilibrium constant K = C _B /C _A = intensity of line B/intensity of line A (determined from the spectrum) where C _A and C _B are the concentrations of the isomers in form A and B, respectively. The concentration of each isomer is, of course, obtained from the intensity of the spectral lines detected from the element representative of the temperature. The use of this technique to measure the temperature in an object, i.e., the measurement of line intensity, provides a similar sensitivity to the technique utilized in the exchange rate method. Furthermore, as in the exchange rate method, the equilibrium constant K, or ratio method, is uniquely specific to individual compounds at particular temperatures. Furthermore, compounds in the slow exchange limit or highly sensitive compounds are generally particularly suitable at physiological temperatures. However, line intensities may vary with varying settings on the apparatus, and will be influenced by experimental conditions, such as pulse rate and sample properties, such as relaxation times associated with the spectral lines under consideration. In this way, temperature measurement by the exchange rate method appears to be more accurate and is therefore a particularly preferred method.

If this is desired, the equilibrium constant K or ratio is established and further calculations are made to determine the enthalpy difference ΔH between the isomers present, which is expressed by the following formula: dK/K/dT =dlnK/dT=ΔH/RT ² (where ΔH corresponds to a compound having two conformers at a particular temperature).

Regarding the spectral line position method, once a spectrum has been obtained for a detected element of a compound with conformers, the difference in horizontal line position for each isomer is representative of temperature. Thus, as the temperature changes, the position of the horizontal line for the isomer of the compound that uniquely characterizes the temperature changes.
However, it should be understood that the linear position method is a reflection of the isomer exchange rate.

The use of spin-spin coupling to measure temperature involves the effect of splitting one resonance into a group of spectral lines. This phenomenon is caused by other magnetized nuclei in the molecule. In effect, these internal magnetized nuclei align in a small number of distinct ways due to the strong applied magnetic field of the device, thereby making several of the magnetic fields as opposed to a single value of the observed nuclei. yields closely spaced values of . Therefore, perturbations in the spectral lines are observed. The number of this perturbation depends on the number of nuclei of a given type undergoing fission and their properties. The spacing between the lines, i.e. the size of the bond, is a property of the nucleus under observation, the nucleus that causes fission,
and depends on the properties of the electrons in the molecule. Furthermore, this effect depends on the type and number of bonds between the interacting nuclei. For example, when a pair of spaced lines, or a doublet, is observed as opposed to a single peak, the spectral line has been split into two. To measure temperature, techniques similar to those used for chemical shifts are used, such as measuring the averaging effect on the bonds or the differences in the positions of the bonds. Such techniques, similar to techniques determined from chemical shifts, are derived from the principle that compounds having at least one conformational isomer interconvert uniquely at different temperatures. However, this procedure is more difficult to implement as a means of accurately measuring temperature, and therefore the use of the exchange rate method described above may be particularly suitable.

Temperature can also be determined by relaxation time. The two most common relaxation times are T ₁ , or spin-lattice relaxation time, and T ₂ , or spin-spin relaxation time. Although each resonance of an element in a compound with conformers has its own particular value of these relaxation times, the individual components of the multiplet, or spin-spin coupling effect, tend to be nearly identical in their relaxation properties. Motsu. Relaxation rate is the reciprocal of relaxation time. T ₁ is a measure of the rate at which the nuclei align with the magnetic field of the device, or the rate at which the nuclear spins reestablish thermal equilibrium (which is not related to heat or equilibrium for the compound). Specifically, the magnetization M of the nucleus typically approaches its ultimate or equilibrium value exponentially. Therefore, T ₁ is the time constant of the exponential function denoted by M in the ultimate M at time ^t . Experimentally, T ₁ determines the rate at which the nucleus can absorb or release energy. For continuous wave procedures, this determines the maximum radio frequency power that can be used without signal loss due to saturation. pulse or
The FT (Fourier Transform) experiment determines the maximum high speed at which pulses can be applied.

T ₂ is a measure of the width of a resonance line in the spectrum and only has meaning in the context of a particular lineament. For example, if the line is Lorentzian: y=
If it has a functional _form of _1/1 + Experimentally, 1/T ₂ is a measure of line width. In an experiment where a pulse was applied,
T ₂ is a measure of the time required for the free induction decay (FID) to gradually subside. Again, if the line has a Lorentzian shape, the FID envelope is exponential and T ₂ is a time constant.

In practice, the NMR spectrum consists of RF pulses, i.e.
FID can be obtained by applying 90° pulses or shorter pulses as desired to obtain the most effective sensitivity, capture these signals, average these signals, and Fourier transform them to obtain a spectrum. . T ₁ can be measured by inversion recovery: 180° pulse, time delay, 90° pulse FID acquisition. The signal magnitude is fit to an experimental function of the delay time to obtain T ₁ . T ₂ can be measured by spin-echo technique: 90° pulse,
Delay, 180° pulse, same delay, signal acquisition. The magnitude of the signal is adjusted to an exponential function of the delay time to obtain T ₂ . Many variations of these procedures have been published and can be used herein in accordance with the principles of the present invention.
If we are trying to determine temperature from relaxation times, for example the difference in T ₁ , the nuclei rearrange,
or the rate at which thermal equilibrium is reestablished, or T ₂ ,
The rate of decay of the FID can be measured as a function of temperature.
The method described herein can be reconfigured to image the temperature at an object. Thus, the change in relaxation time is uniquely characteristic for determining temperature from a given compound over the applicable temperature range.

Accordingly, the broadest aspect of the present invention is to provide a new and improved method of indirectly sensing the temperature of at least one object using NMR techniques. More specifically, the method uses chemical shifts, relaxation times, and chemical shifts for detected elements of a compound having conformers in an object that are influenced by at least one temperature of the object to determine the temperature. , to obtain NMR spectra to measure spin-spin coupling and quadrupolar coupling. In another broad embodiment, the present invention, in accordance with its principles and teachings, can be used to sense the temperature of an animal. In yet another broad embodiment, the invention describes the exchange rate k, the equilibrium constant K, the difference in the horizontal position of the spectral lines, the difference in relaxation times, e.g. T ₁ and T ₂ , the difference in spin-spin coupling, and the quadrupole The temperature can be determined from the difference in bonding. In yet another broad embodiment, the invention provides a means for sensing and monitoring the thermal state of an object from chemical shifts, relaxation times, e.g. T ₁ or T ₂ , spin-spin coupling or quadrupolar coupling. Alternatively, the temperature of at least one object or animal can be imaged as a means of sensing and monitoring the thermal and physiological state of the animal. In yet another broad embodiment, the invention can be used to sense and image temperature in solids or liquids as defined herein. The method of the present invention is unique because it is non-invasive, non-destructive, and non-ionizing to the object or animal. Furthermore, the present invention can be used continuously to obtain the above measurements or results. A novel method of sensing the temperature of at least one object in accordance with the principles of the present invention comprises subjecting said object to an NMR spectrometer;
detecting a radio frequency signal in a spectral pattern derived from an element of the compound in which the compound has at least one conformer that is affected by temperature;
and comparing this signal to detect at least one temperature. The signals detected for an element correspond to spectral positions or chemical shifts representative of conformational isomers of the compound. In terms of chemical shifts or spectral positions, the difference between spectral positions corresponds to the chemical exchange rate k between the conformers representative of that temperature. Moreover, the difference between spectral positions is itself representative of said temperature. Furthermore, the intensity of the spectral lines is also representative of said temperature under appropriate conditions. Since the effect of shielding is different for each isomeric form, different signals are detected for the detected element depending on its spectral position or chemical shift. Therefore, the exchange rate k, the equilibrium constant K, the difference in horizon position and the difference in relaxation time, quadrupole coupling and spin-spin coupling can be interpreted to correspond to at least one temperature of the object. The most suitable method for sensing temperature according to the principles of the method of the invention is the exchange rate k method.

It is understood that various spectra will be obtained for the radio waves emitted by the detected elements of a compound in the presence of a certain temperature, and that such spectra can be contrasted with those obtained at known standard temperatures. There will be. In this way, various spectra provide a means of temperature sensing or measurement that affects the spectra of detectable nuclei. Measurements of chemical shifts, relaxation times, spin-spin coupling and quadrupolar coupling provide parameters representative of temperature. For example, the determined exchange rate k, the equilibrium constant K, and the difference in horizon position, as well as the relaxation time, spin-spin coupling, and quadrupolar coupling, are each known variables independently of a subject as a means of temperature determination. Comparisons are made with standard exchange rates k, equilibrium constants K, and horizontal line positions, relaxation times, spin-spin coupling and quadrupolar coupling determined and established for the elements of the compound as influenced by temperature. However, when using a calibration method, the signal detected for an element in a compound regardless of the object is determined by the standard exchange rate k for that compound element, the equilibrium constant K, the difference in horizontal line position, It must be pointed out that in order to determine and establish the relaxation times, spin-spin coupling and quadrupole coupling, it is good to be influenced by a known temperature and in an environment similar to that in the object. In another technique, the temperature can be calibrated to be determined directly from the calculated parameters listed herein.

Furthermore, the thermal map of an in-vivo object or animal can be determined by chemical shift, relaxation time, e.g. T ₁
T ₁ or T ₂ derived from inversion recovery for T ₂ and from spin-echo, spin-spin coupling and quadrupolar coupling can be obtained as one-dimensional, two-dimensional, or three-dimensional images.
Measurement and imaging of inanimate and living solids and liquids can also be performed in accordance with the principles of the present invention. The term solid refers to solids and semi-solids, such as gels and biological solids in plants, tissues, etc.

In another aspect of the invention, fluorine is currently the best element to detect in objects or animals as a means of indirectly sensing temperature. As mentioned in the background, fluorine is NMR
It is uniquely suited to the technology because fluorine has a spin of 1/2, gives relatively uncomplicated, well-resolved narrow spectral lines, has a natural isotope abundance of 100%, This is because they have a large chemical shift, a magnetic rotational constant similar to that of protons (thus allowing the same equipment to be used), and a relatively low natural biological abundance in a form that can be observed by conventional NMR techniques. To follow the teachings of the present invention, a sufficient amount of the fluorine-containing compound must be introduced into the subject or animal so that the fluorine can be detected by NMR techniques. Introducing herein refers to administration of a compound by inhalation, injection, oral introduction or other suitable means. Furthermore, such fluorine compounds must be chemically compatible with the object or animal, physically compatible with the formation of compositions that can be suitably introduced into the object, and have a chemical shift. Alternatively, it must provide a distinct NMR signal that is easily distinguishable so that spectral shifts can be measured accurately. Perfluorinated hydrocarbons and their derivatives have been found to be ideally suited for application in accordance with the principles of the present invention. Regarding the compounds presented here, they are relatively incompatible with their surrounding environment in the sense that they do not mix with or react with it, and therefore give chemical shifts that reliably correspond to temperature. Will. Another advantage of these compounds is that they allow for easy determination of chemical shifts derived from isomers of these compounds that are influenced by at least one temperature in the object or animal. It must give a distinguishable signal to the Particularly suitable perfluorinated hydrocarbons or derivatives thereof that can be used in accordance with the teachings of the present invention are perfluorocyclic hydrocarbons or emulsions thereof, such as those used in artificial blood. Nevertheless, any perfluorinated hydrocarbon or derivative thereof exhibiting sparse RES properties as defined in US Pat. Nos. 3,911,138 and 4,105,798 can be used in the process of the present invention. Such compounds include perfluoro(methylcyclohexane), perfluoro-1-methyldecalin [also known as perfluoro(decahydro-a-methylnaphthalene)], perfluoro(1,
3-dimethylcyclohexane), perfluoro(decahydronaphthalene), and perfluoro(decahydrodimethylnaphthalene), or mixtures thereof, perfluorinated bicyclononane, perfluorinated bicyclooctane, perfluorinated adamantane, perfluoromethyladamantane, and perfluorinated adamantane. Dimethylbicyclo[3.3.1]nonane, perfluorodimethyladamantane and perfluorotrimethylbicyclo[3.3.1]nonane, perfluorotetrahydrodicyclopentadiene, perfluorinated bicyclononane, perfluorinated bicyclooctane, perfluorinated adamantane, perfluoromethyl Adamantane and perfluorodimethylbicyclo[3.3.1]nonane, perfluorodimethyladamantane and perfluorotrimethylbicyclo[3.3.1]nonane, and perfluorotetrahydrodicyclopentadiene and perfluorobicyclo[5.3.1]decane, and perfluorotributylamine (FC47) , perfluorodecalin (PP5), perfluorotetrahydrofuran (FC80), perfluoroether (PID)
[(CF ₃ ) ₂ CFOCF ₂ (CF ₂ ) ₂ CF ₂ OCF (CF ₃ ) ₂ ], perfluoroether (PD) [(CF ₃ ) ₂ CFOCF ₂
(CF ₂ ) ₆ CF ₂ OCF (CF ₃ ) ₂ ], perfluoropolymer (E3) Perfluoropolymer (E4) [(CF ₃ CHF (OCF ₂ CF) ₃ OCF ₂ CF ₂ CF ₃ ], Perfluoroether polymer (Fumbulin Y/01),
Perfluorododecane, perfluorobicyclo[4.3.0] nonane, perfluorotrimethylcyclohexane, perfluoroisopropylcyclohexane, perfluoroendotetrahydrodicyclopentadiene, perfluorobicyclo[5.3.0]
Decane, perfluorotetramethylcyclohexane, perfluoro-1-methyl-4-isopropylcyclohexane, perfluoro-n-butylcyclohexane, perfluorodimethylbicyclo[3.3.1]nonane, perfluoro-1-methyladamantane, perfluoro-1-methyl-4- t-
Butylcyclohexane, perfluorodecahydroacenaphthylene, perfluorotrimethylbicyclo[3.3.1]nonane, perfluoro-n-undecane, perfluorotetradecahydrophenanthrene, perfluoro-1,3,5,7-tetramethyladamantane, perfluorododeca Hydrofluorene, perfluoro-1,3-dimethyladamantane, perfluoro-n-octylcyclohexane, perfluoro-7-methylbicyclo[4.3.0]nonane, perfluoro-p-diisopropylcyclohexane, and perfluoro-m-
Diisopropylcyclohexane, and perfluorocyclic hydrocarbons, such as perfluoro(methylcyclohexane), perfluoro(1,3-dimethylcyclohexane), perfluoro(decahydronaphthalene), perfluoro(decahydro-
1-methylnaphthalene), and perfluoro(decahydrodimethylnaphthalene), or mixtures thereof, perfluorinated bicyclononane, perfluorinated bicyclooctane, perfluorinated adamantane hydrocarbons, perfluoromethyladamantane and perfluorodimethylbicyclo [3.3. 1] Nonane, perfluorodimethyladamantane and perfluorotrimethylbicyclo [3.3.1] Nonane, perfluorotetrahydrodicyclopentadiene and perfluorobicyclo [5.3.0] Decane, perfluorotetrahydrodicyclopentadiene, perfluorinated bicyclononane, perfluorinated bicyclo Included are octane, perfluorinated adamantane, perfluoromethyladamantane and perfluorotrimethylbicyclo[3.3.1]nonane, and perfluorotetrahydrodicyclopentadiene and perfluorobicyclo[5.3.0]decane.

According to this description and presently particularly suitable embodiments:
It will be clear that elements other than fluorine can be chosen to sense the temperature of at least one object. For example, based on the sensitivity and validity requirements for current NMR techniques, other elements with these properties, specifically aluminum-27, boron-11, carbon-13, chlorine-35, chlorine-37, deuterium , magnesium-25, nitrogen-14, nitrogen-15, oxygen-17, phosphorus-31, platinum-195, protons, silicon-29 and sodium-23, and other similar elements.

In another aspect of the invention, one temperature or several temperatures can be detected in an object or animal. Therefore, the invention can be used to measure temperature fluctuations and distributions. In another aspect of the invention, due to the non-invasive, non-ionizing and non-destructive nature of NMR technology, the novel method according to the invention can be used continuously.
Furthermore, the magnetic fields to be used in the method of the present invention can be created by iron core, resistive air core, and superconducting air core magnet designs. According to the principles of the invention, low resolution and high resolution NMR can be used. Of course, as the resolution increases, the spectrum will become better resolved and more defined for the detected elements. Therefore, whenever possible, high-resolution NMR is used to detect elements in compounds. During inspection, spectral overlap or overlapping is undesirable according to the teachings of the present invention and will typically not be observed when detecting fluorine, for example. Furthermore,
The method of the invention can be used to measure and monitor thermal physiological conditions in animals and to measure and monitor thermal conditions in objects. The fundamental advantage of such an application is to provide the medical and biological community with a reliable analytical tool for animal diagnostic purposes. Another advantageous embodiment of the method is that it is used to detect a signal for temperature-affected elements in at least one region of an animal or object that corresponds to a temperature distribution of the animal or object. It is. In this way, physiological temperatures or temperature conditions in various regions of the animal or object can be determined.

In another aspect of the invention, the indirectly sensed temperature is determined by a chemical shift, relaxation, derived from a detected element of a compound affected by at least one temperature in one or more regions of an object. It can be uniquely and advantageously imaged into one-, two-, or three-dimensional projections reconstructed from time, e.g., inversion recovery T ₁ , or spin-echo T ₂ , or spin-spin coupling. This objective is achieved in accordance with some principles of the present invention by spatially defining detected elements in an object influenced by at least one temperature.
For example, a detection signal in an object may be for at least one region in the object, or multiple individual portions along at least one region. Furthermore, the area may constitute a strip, and the signal may be detected for a number of individual portions, each along at least one strip in the object. Furthermore, the region may represent at least one substantially planar slice or a series of parallel planar slices in the object. If a spatial distribution within at least one slice is desired, the signal can be detected for at least one strip or for multiple strips perpendicular to the slice. To further clarify the spatial distribution of temperature-influenced elements in an object, signals can each be detected for at least one portion along at least one of the strips and at least one of the slices. Furthermore, the regions may also constitute host tissue in at least one area of interest in the object. Methods of defining spatial resolution are well known, and one or more use magnetic field gradients to distinguish areas where similar elements are located. Any of the teachings for obtaining temperature-influenced spatial distributions of elements can be used with the principles of the present invention as long as they do not depart from the subject matter. An example of obtaining a spatial distribution is, for example, U.S. Patent No.
No. 4297637, No. 4318043 and No. 4361807. Once the spatial distribution of an element as affected by temperature is observed, the NMR projection can be reconstructed from the element's chemical shift, relaxation time, spin-spin coupling, and quadrupolar coupling. Such methods include zoom tomography, NMR tomography, surface coil techniques, and chemical microscopy [Hall, L.; Day. (Hall, LD) and Sukumar, S.: Chemical
Microscopy using a High-Resolution
NMR Spectrometer.A Combination of
Tomography/Spectroscopy Using Either ¹ H
or ¹³ C.50:161-164 (1982)]
including. Among these methods, Lauterbur et al.: Zeugmatographic High
Resolution Nuclear Magnetic Resonance
Spectroscopy Images of Chemical
Inhomogeneity Within Macroscropic Objects.
J. American Chemical Society.97(23):6866~
6868, November 12, 1975, Brown
The methods described in US Pat. No. 4,319,190 and Burl et al., US Pat. No. 4,361,807 are particularly good for imaging from chemical shift reconstructions, and the methods taught by Lauterbourg and Brown are even better. However, any imaging technique compatible with the method taught by the present invention can be used, such as imaging from projection, FONAR, sensitive point imaging, Fourier imaging, and selective illumination imaging. As already mentioned, the temperature in a given object or animal can also be determined by such applicable techniques that the observed relaxation time from the detected element is affected by the temperature in the object, preferably a reversal recovery from T ₁ , Alternatively, it can be imaged from spin-echo, spin-spin coupling, and quadrupole coupling from _T2 . In yet another aspect of the present invention, temperatures in inanimate or living solids or liquids can be determined and imaged in accordance with the teachings herein.

Example: A small amount of 1,1,2,2-tetrafluorocyclohexane is operated at a magnetic field strength of approximately 7500 Gauss.
Introduce into NMR imaging spectrometer. Temperature about -20℃
Fluorine-19 NMR spectra were obtained at each temperature by changing the temperature by 0.5℃, and from each spectrum, the value of the chemical shift difference between the spectral lines corresponding to the axial and equatrile conformer positions of fluorine in this compound was determined in Hz. Record and create a scale table of chemical shifts and corresponding temperatures. This compound has been described by Roberts, J. Day.
(Roberts, JD): Studies of Conformational
Equilibria and Equilibration by Nuclear
Magnetic Resonance Spectroscopy.Chem.
As described in Britain 2:529-535, (1966),
It has an activation energy of approximately 8.0 kcal mol ^-1 for this interconversion. The maximum spectral separation under these conditions is approximately 500Hz. Around -20°C, this separation changes by about 50Hz/°C.

The compound is then introduced into the object whose temperature is to be mapped. A fluorine chemical shift image of the object is obtained according to Brown, US Pat. No. 4,319,190. Temperature values are calculated at each volume element of the image by measuring the spectral separation in the NMR spectrum for each volume element using an automated computer method and deriving the temperature by interpolation from a calibration table.

This method does not add measurement time over that of chemical shift imaging methods. The computer processing time required to derive the temperature is small compared to the image reconstruction time in two dimensions, and is of little concern in the three-dimensional case.

Another method would be to fit the line to the calibration line, but this would require a substantial amount of computer processing time. This may be practical if you are trying to measure temperature at a very small number of points.

In view of the above detailed description and particularly suitable embodiments, it will be understood that the invention may be carried out in other specific ways than those herein described without departing from the spirit and essential characteristics thereof. Maybe. Therefore, these specific examples are to be regarded in all respects as illustrative and not as limiting. All changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims (1)

[Scope of Claims] 1. A method for measuring the temperature of an object, wherein the exchange process between conformers is at least two conformers that undergo such an exchange process that is influenced by temperature. subjecting an object containing a compound with one form to an NMR spectrometer, exposing the compound to a temperature that affects the exchange process, and deriving from the nuclear magnetic resonance of the elements in the compound undergoing the affected exchange process. 2. A method according to claim 1, characterized in that said radio frequency signal is detected and processed as a temperature measurement. 2. The method according to claim 1, wherein the object is an animal. 3. The method according to claim 1, wherein the object is a solid. 4. The method according to claim 1, wherein the object is a liquid. 5. The method of claim 1, wherein the detected signal for the element corresponds to a spectral position representative of a conformational isomer of the compound. 6. The method according to claim 1, wherein the temperature is determined from the relaxation time derived from the detected element of the compound. 7. The method of claim 1, wherein the temperature is determined from spin-spin coupling derived from detected elements of the compound. 8. The method of claim 1, wherein the temperature is determined from the quadrupole coupling derived from the detected element of the compound. 9. The method according to claim 1, wherein the element to be detected is fluorine. 10. The method of claim 1, wherein the element is selected from the group consisting of aluminum, boron, carbon, chlorine, magnesium, nitrogen, oxygen, phosphorus, platinum, hydrogen, silicon, and sodium. 11. The method according to claim 1, which detects temperature within a tissue. 12. The method according to claim 1, which detects temperature in blood. 13. The method according to claim 1, which continuously detects temperature. 14. The method of claim 1, wherein a signal detected for an element in the object that is influenced by temperature is determined for at least one region of the object. 15. Claim 1, wherein at least one of the determined regions is a strip in the object.
The method described in Section 4. 16. The method according to claim 1, wherein the temperature state of the object is measured while being monitored. 17. The method of claim 1, wherein the spectral pattern is indicative of the temperature of the object. 18 A method for detecting the temperature of at least one in an object, the method comprising: subjecting the object to an NMR spectrometer; detecting a radio frequency signal in the temperature-influenced spectral pattern of the fluorine element derived from a dielectric; Said method, characterized in that it is compared with that of a standard NMR spectral pattern established for said element. 19. The method according to claim 18, wherein a fluorinated hydrocarbon or a derivative thereof is introduced into an object. 20. The method according to claim 18, wherein a fluorinated hydrocarbon or a derivative thereof is introduced into an animal. 21 Perfluorinated hydrocarbons or their derivatives are
19. The method according to claim 18, which is RES property. 22. The method of claim 18, wherein the fluorinated hydrocarbon or derivative thereof is in aqueous form. 23 Perfluorinated hydrocarbons or their derivatives are perfluoro(methylcyclohexane), perfluoro-1-methyldecalin [also known as perfluoro(decahydro-a-methylnaphthalene)], perfluoro(1,3-dimethylcyclohexane), perfluoro( decahydronaphthalene), and perfluoro(decahydrodimethylnaphthalene), or mixtures thereof, perfluorinated bicyclononane, perfluorinated bicyclooctane, perfluorinated adamantane, perfluoromethyladamantane and perfluorodimethylbicyclo[3.3.1]nonane , perfluorodimethyladamantane and perfluorotrimethylbicyclo[3.3.1]nonane, perfluorotetrahydrobicyclopentadiene, perfluorinated bicyclononane,
Perfluorinated bicyclooctane, perfluorinated adamantane hydrocarbon, perfluoromethyladamantane and perfluorodimethylbicyclo [3.3.1]
nonane, perfluorodimethyladamantane and perfluorotrimethylbicyclo[3.3.1]nonane, and perfluorotetrahydrodicyclopentadiene and perfluorobicyclo[5.3.1]decane, and perfluorotributylamine (FC47), perfluorodecalin (PP5),
Perfluorotetrahydrofuran (FC80), perfluoroether (PID) [(CF ₃ ) ₂ CFOCF ₂
(CF ₂ ) ₂ CF ₂ OCF (CF ₃ ) ₂ ], perfluoroether (PIID) [(CF ₃ ) ₂ CFOCF ₂ (CF ₂ ) ₆ CF ₂ OCF
(CF ₃ ) ₂ ], perfluoropolymer (E3) Perfluoropolymer (E4) [CF ₃ CHF
(OCF ₂ CF) ₃ OCF ₂ CF ₂ CF ₃ ], perfluoroether polymer (Fumbulin Y/01), perfluorododecane, perfluorobicyclo[4.3.0]nonane, perfluorotrimethylcyclohexane, perfluoroisopropylcyclohexane, perfluoroendotetrahydrodicyclo Pentadiene, perfluorobicyclo[5.3.0]decane, perfluorotetramethylcyclohexane, perfluoro-1-methyl-4-isopropylcyclohexane, perfluoro-n-butylcyclohexane, perfluorodimethylbicyclo[3.3.1]nonane, perfluoro-1-methyladamantane ,
Perfluoro-1-methyl-4-t-butylcyclohexane, perfluorodecahydroacenaphthylene, perfluorotrimethylbicyclo [3.3.1]
Nonane, perfluoro-n-undecane, perfluorotetradecahydrophenanthrene, perfluoro-1,3,5,7-tetramethyladamantane, perfluorododecahydrofluorene, perfluoro-1,3-dimethyladamantane, perfluoro-n-octylcyclohexane , perfluoro-7-methylbicyclo[4.3.0]nonane,
Perfluoro-p-diisopropylcyclohexane, and perfluoro-m-diisopropylcyclohexane, and perfluorocyclic hydrocarbons, such as perfluoro(methylcyclohexane), perfluoro(1,3-dimethylcyclohexane), perfluoro(decahydronaphthalene), perfluoro(decahydro- 1-methylnaphthalene) and perfluoro(decahydrodimethylnaphthalene), or mixtures thereof, perfluorinated bicyclononane, perfluorinated bicyclooctane, perfluorinated adamantane hydrocarbons, perfluoromethyladamantane and perfluorodimethylbicyclo [3.3.1 ] Nonane, perfluorodimethyladamantane and perfluorotrimethylbicyclo [3.3.1] Nonane, perfluorotetrahydrodicyclopentadiene and perfluorobicyclo [5.3.0] Decane, perfluorotetrahydrodicyclopentadiene, perfluorinated bicyclononane, perfluorinated bicyclooctane , perfluorinated adamantane, perfluoromethyladamantane and perfluorotrimethylbicyclo[3.3.1]nonane, and perfluorotetrahydrodicyclopentadiene and perfluorobicyclo[5.3.0]decane. the method of. 24. A method for measuring a thermal physiological state in an animal, the method comprising: determining at least two forms of conformers in which the exchange process between the conformers is subject to such an exchange process that is influenced by temperature; subjecting an animal containing a compound to an NMR spectrometer, exposing the compound to a temperature that affects the exchange process, and subjecting the compound to a radio frequency derived from the nuclear magnetic resonance of an element in the compound undergoing the affected exchange process. Said method, characterized in that the signal is detected and processed as a temperature measurement. 25. The method according to claim 24, wherein the thermal physiological state in the animal is measured while being monitored.